The need to treat elusive and debilitating disorders such as cancer, osteoporosis and other diseases involving untoward bone resorption (e.g., Paget""s Disease, primary and secondary hyperparathyroidism, humoral hypercalcemia of malignancy, various cancers where resorption is increased, and rheumatoid arthritis), and disorders involving increased vascular permeability, to name a few, has led to extensive research on the mechanisms involved in disease initiation and/or progression and on the identification of new drugs which might interfere with those mechanisms.
One approach, for example, for treating bone disorders is inhibition of the osteoclast proton pump. See e.g., Blair et al., Science 1989, 245, 855-857; Finbow et al., Biochem. J. 1997, 324, 697-712; Forgac, M. Soc. Gen. Physiol. Ser. 1996, 51, 121-132; Baron et al., J. Cell. Biol. 1985, 101, 2210-2222; Farina et al., Exp. Opin. Ther. Patents 1999, 9, 157-168; and David, P. and Baron, R. xe2x80x9cThe Vacuolar II+-ATPase: A Potential Target for Drug Development in Bone Diseasesxe2x80x9d Exp. Opin. Invest. Drugs 1995, 4, 725-740.
Another approach to drug discovery for treating bone-related (and other) diseases involves the control of cellular signal transduction. See, for example, Missbach et al., xe2x80x9cA Novel Inhibitor of the Tyrosine Kinase Src Suppresses Phosphorylation of Its Major Cellular Substrates and Reduces Bone Resorption In Vitro and in Rodent Models In Vivo.xe2x80x9d Bone 1999, 24, 437-449; Connolly et al., Bioorg. and Med. Chem. Lett. 1997, 7, 2415-2420; Trump-Kallmeyer et al., J. Med. Chem. 1998, 41, 1752-1763; Klutchko et al., J. Med. Chem. 1998, 41, 3276-3292; Legraverend et al., Bioorg. and Med. Chem. 1999, 7, 1281-1293; Chang et al., Chem. and Biol. 1999, 6, 361-375; Lev et al. Nature 1995, 376, 737-784; Palmer et al., J. Med. Chem. 1997, 40, 1519-1529.
Some approaches for the treatment of bone disorders such as osteoporosis include, for example, estrogens, bisphosphonates, calcitonin, flavonoids, and selective estrogen receptor modulators. Other approaches include peptides from the parathyroid hormone family, strontium ranelate, and growth hormone and insulin-like growth response (see, for example, Reginster et al. xe2x80x9cPromising New Agents in Osteoporosis,xe2x80x9d Drugs R and D 1999, 3, 195-201). Unfortunately, these therapetic agents still have significant shortcomings.
The variety of different approaches represented by the therapeutic agents currently available or under study evidence the variety of biological factors influencing the competing processes of bone production and resorption. Although progress has been made towards developing therapeutic agents for osteoporosis and other bone disorders, there remains a need to develop new therapeutic agents which have an improved therapeutic index, which may be given to patients who cannot well tolerate or do not respond to existing therapies, and/or which may be used in conjunction with other therapies.
Protein kinases, specifically Src protein kinases, have been shown to play a crucial role in osteoclast function and thus in the resorption of bone and the progression of the osteoporosis. In addition, cellular signal transduction mediated by kinases like Src is believed to play a key role in other diseases, for example cancer and diseases involving increased vascular permeability. Though the exact mechanisms of signal transduction is still unclear, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation.
Several families of protein tyrosine kinases have been implicated in human cancer, including, but not limited to Src, Abl, Jak, Ack, Csk, Fak, Fes, Frk, Tec, and Syk, to name a few. For a detailed review of the role of oncogenic kinase signalling see, Blume-Jensen et al. Nature, 2001, 411, 355, and references cited therein.
Furthermore, certain kinases are believed to mediate signaling activity in response to a variety of growth factors, including VEGF, vascular endothelial growth factor, (see, Schlessinger, J. Cell 2000, 100, 293; Lowell et al. Genes Dev. 1996, 10, 1845), which is an angiogenic factor that promotes vascular permeability. The ability to control (and/or diminish) increased vascular permeability by suppression of a signalling pathway would be useful for the treatment of patients suffering from diseases and conditions related to increases in vascular permeability (e.g., edema, hemorrhage, cancer, vasular leaks, and the like). For a review of antiangiogenic agents (including those agents having antitumor activity), see Klohs et al., Curr. Opin. Biotechnol. 1999, 10, 544.
Although some progress has been made in the treatment of certain debilitating diseases and disorders mentioned herein, there remains a need to develop new therapeutic agents which have an improved therapeutic index, which may be given to patients who cannot well tolerate or do not respond to existing therapies, and/or which may be used in conjunction with other therapies. Thus, new, selective inhibitors of osteoclast activity and promoters of osteoblast activity as well as therapeutic agents that can regulate a variety of other signal transduction pathways would be desirable. Such compounds may then be used to inhibit or promote complex biological processes in order to treat and/or prevent diseases associated with signalling (e.g., osteoporosis, cancer and edema, to name a few).
As discussed in more detail herein, there remains a need for the development of novel therapeutics useful for the treatment of bone related disorders, cancer, and signalling disorders generally. There is also a particular need for the development of selective therapeutic agents (e.g. those that can selectively target bone, or that can selectively inhibit or promote cellular signaling pathways).
1. General Description of Compounds of the Invention:
In recognition of the need to develop more selective and potent therapeutic agents, the present invention provides a novel family of quinolinones that have a broad range of useful biological and pharmacological properties.
These include compounds having the general formula I (and pharmaceutically acceptable derivatives thereof): 
wherein the dotted line represents an optional bond;
X is O, S or NRH;
RA is hydrogen, oxygen, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
RB is an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
RC is hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; halogen; cyano; alkyloxycarbonyl; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, and wherein each occurrence of RL and RM is independently hydrogen, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
RD is an aryl or heteroaryl moiety;
each occurrence of R9 and R5 is independently hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; cyano; xe2x80x94C(O)RJ; xe2x80x94C(O)ORJ; xe2x80x94NRJC(O)ORK; xe2x80x94OC(O)RJ; xe2x80x94NRJSO2RK; xe2x80x94SO2NRJRK; xe2x80x94NRJC(O)RK; xe2x80x94C(O)NRJRK; xe2x80x94CHxe2x95x90NORJ; xe2x80x94S(O)nRJ, wherein n is an integer from 0 to 2; xe2x80x94(CRLCRM)uxe2x80x94Cxe2x89xa1CRJ; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
R7 is hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; cyano; xe2x80x94C(O)RJ; xe2x80x94C(O)ORJ; xe2x80x94NRJC(O)ORK; xe2x80x94OC(O)RJ; xe2x80x94NRJSO2RK; xe2x80x94SO2NRJRK; xe2x80x94NRJC(O)RK; xe2x80x94C(O)NRJRK; xe2x80x94CHxe2x95x90NORJ; xe2x80x94S(O)nRJ, wherein n is an integer from 0 to 2; xe2x80x94(CRLCRM)uxe2x80x94Cxe2x89xa1CRJ; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
u is an integer from 0-6;
AK is (CRPCRQ);
each occurrence of RP and RQ is independently hydrogen or an aliphatic moiety;
q is an integer from 0 to 5;
p is an integer from 0-3;
r is an integer from 0-2;
R9a is hydrogen; or an aliphatic or heteroaliphatic moiety;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted; and
at least one of RB or RD as defined above, comprises a phosphorus-containing moiety.
In certain embodiments, compounds described generally above have the limitation that:
(1) if q is 0; and RB comprises the only phosphorus-containing moiety PCM and PCM is xe2x80x94P(xe2x95x90O)ORxe2x80x2Rxe2x80x3, or if R9a is xe2x80x94C1-6alkylP(xe2x95x90O)ORxe2x80x2ORxe2x80x3; wherein Rxe2x80x2 and Rxe2x80x3 are independently hydrogen, C1-6alkyl, xe2x80x94(CRxRy)xcfx89xe2x80x94C3-10cycloalkyl or arylC1-6alkyl; wherein w is an integer from 0-5 and Rx and Ry are independently hydrogen or C1-6alkyl; then RB is not phenyl; and
(2) if q is 0; and RB and RD are each phenyl, then neither RB nor RD is substituted with xe2x80x94P(xe2x95x90O)ORxe2x80x2Rxe2x80x3; and R9a is not xe2x80x94C1-6alkylP(xe2x95x90O)ORxe2x80x2ORxe2x80x3; wherein Rxe2x80x2 and Rxe2x80x3 are independently hydrogen, C1-6alkyl, xe2x80x94(CRxRy)xcfx89xe2x80x94C3-10cycloalkyl or arylC1-6alkyl; wherein w is an integer from 0-5 and Rx and Ry are independently hydrogen or C1-6alkyl.
It will be appreciated that the compounds of the present invention are intended to encompass structures having a variety of phosphorus-containing moieties; however, in certain embodiments, one or more of RB-RD, as defined above or herein, are substituted with one or more phosphorus moieties each independently a group having a structure from Series I below: 
wherein each occurrence of K is independently O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1);
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94 or (M)x;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6; and
each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.
In certain embodiments, M is xe2x80x94CRxRy, wherein each occurrence of Rx and Ry is independently hydrogen, halogen, alkyl, heteroalkyl, ORL or NRLRM; wherein each occurrence of RL and RM is independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety. In certain exemplary embodiments, R1 is hydrogen or lower alkyl and M is xe2x80x94CH2xe2x80x94, xe2x80x94CH(OH)xe2x80x94, xe2x80x94CH(NH2)xe2x80x94, xe2x80x94C(alkyl)(OH)xe2x80x94, xe2x80x94C(alkyl)(NH2)xe2x80x94, xe2x80x94CH(halo)- or xe2x80x94C(halo)2-.
Exemplary phosphorus-containing moieties are further illustrated by the groups of Series Ia and Ib below: 
wherein each occurrence of K is independently O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1);
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94 or (M)x;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6; and
each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted; and
each occurrence of R4 is independently an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.
Exemplary phosphorus-containing moieties are further illustrated by Series Ic depicted below: 
wherein each occurrence of R1 is independently hydrogen, alkyl or aryl;
each occurrence of R4 is independently alkyl or aryl;
each occurrence of R6 is independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; and
each occurrence of R8 is independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, or a prodrug moiety;
wherein in each of the foregoing groups each alkyl or heteroalkyl moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.
Exemplary phosphorus-containing moieties are further illustrated by Series II depicted below: 
wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2; and each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6;
PCM is a phosphorus-containing moiety of Series I, Series Ia, Series Ib; or Series Ic, and m is an integer from 0-3, t is an integer from 1-3, and the sum of m+t is an integer from 1-5;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.
Exemplary phosphorus-containing moieties are further illustrated by Series IIa below: 
wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1); wherein each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6;
m is an integer from 0-3; and
PCM is a phosphorus-containing moiety of Series I, Series Ia, Series Ib or Series Ic;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.
Exemplary phosphorus-containing moieties are further illustrated by Series IIb below: 
wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1);
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x;
each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6; and
m is an integer from 0-3;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.
Exemplary phosphorus-containing moieties are further illustrated by Series III below: 
wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2; each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x; and m is an integer from 0-4;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6;
each occurrence of R6 is independently hydrogen, aliphatic, heteroaliphatic, aryl or heteroaryl moiety; and
each occurrence of R8 is independently hydrogen, an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or a prodrug moiety;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.
Certain exemplary embodiments are described in more detail below and in the examples; however, it will be appreciated that the compounds of the invention are not limited by these examples.
2. Certain Featured Classes of Compounds of the Invention:
As discussed above, any one or more of RA-RB or RD, as defined herein, comprise or are substituted with one or more phosphorus-containing moieties.
It will be appreciated that in certain embodiments, RA is hydrogen or lower alkyl and RB, independently for each occurrence is an aliphatic, heteroaliphatic, aryl or heteroaryl moiety and comprises or is substituted with at least one of the phosphorus-containing moieties in Series I depicted below: 
wherein each occurrence of K is independently O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1);
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94 or (M)x;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6; and
each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted.
In certain embodiments, compounds described generally above have the limitation that:
(1) if q is 0; and RB comprises the only phosphorus-containing moiety PCM and PCM is xe2x80x94P(xe2x95x90O)ORxe2x80x2Rxe2x80x3, or if R9a is xe2x80x94C1-6alkylP(xe2x95x90O)ORxe2x80x2ORxe2x80x3; wherein Rxe2x80x2 and Rxe2x80x3 are independently hydrogen, C1-6alkyl, xe2x80x94(CRxRy)xcfx89xe2x80x94C3-10cycloalkyl or arylC1-6alkyl; wherein w is an integer from 0-5 and Rx and Ry are independently hydrogen or C1-6alkyl; then RB is not phenyl; and
(2) if q is 0; and RB and RD are each phenyl, then neither RB nor RD is substituted with xe2x80x94P(xe2x95x90O)ORxe2x80x2Rxe2x80x3; and R9a is not xe2x80x94C1-6alkylP(xe2x95x90O)ORxe2x80x2ORxe2x80x3; wherein Rxe2x80x2 and Rxe2x80x3 are independently hydrogen, C1-6alkyl, xe2x80x94(CRxRy)xcfx89xe2x80x94C3-10cycloalkyl or arylC1-6alkyl; wherein w is an integer from 0-5 and Rx and Ry are independently hydrogen or C1-6alkyl.
It will be appreciated that in certain other embodiments, RA is hydrogen or lower alkyl and RD is aryl or heteroaryl moiety and comprises or is substituted with at least one of the phosphorus-containing moieties in Series I depicted below: 
wherein each occurrence of K is independently O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1);
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94 or (M)x;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6; and
each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted.
In certain other embodiments, compounds as described generically above and as described in certain subsets herein, RA is hydrogen or lower alkyl and either or both of RB and RD comprises or is substituted with one or more of the following phosphorus-containing moieties of Series Ia or Ib depicted below: 
wherein each occurrence of K is independently O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1);
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94 or (M)x;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6;
each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted; and each occurrence of R4 is independently an aliphatic, heteroaliphatic, aryl or heteroaryl moiety. In certain embodiments, M is xe2x80x94CRxRy, wherein each occurrence of Rx and Ry is independently hydrogen, halogen, alkyl, heteroalkyl, ORL or NRLRM; wherein each occurrence of RL and RM is independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety. In certain exemplary embodiments, M is xe2x80x94CH2xe2x80x94, xe2x80x94CH(OH)xe2x80x94, xe2x80x94CH(NH2)xe2x80x94, xe2x80x94C(alkyl)(OH)xe2x80x94, xe2x80x94C(alkyl)(NH2)xe2x80x94, xe2x80x94CH(halo)- or xe2x80x94C(halo)2-.
In still other embodiments, RA is hydrogen or lower alkyl and either or both of RB and RD, as described directly above, comprises or is substituted with at least one of the phosphorus-containing moieties in Series Ic depicted below: 
wherein each occurrence of R1 is independently hydrogen, alkyl or aryl;
each occurrence of R4 is independently alkyl or aryl;
each occurrence of R6 is independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; and
each occurrence of R8 is independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, or a prodrug moiety.
In certain embodiments, R6 is hydrogen, lower alkyl, ORL or NRLRM; wherein each occurrence of RL and RM is independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety. In certain other embodiments, R6 is hydrogen, methyl, ethyl, OH or NH2. In certain embodiments, R8 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl or a prodrug moiety. In still other embodiments, R8 is hydrogen, methyl, ethyl, or a prodrug moiety.
It will be appreciated that, in certain embodiments, RA is hydrogen or lower alkyl and either or both of RB or RD comprises or is substituted with any one of the phosphorus-containing aryl of heteroaryl moieties of Series II: 
wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2; and each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6;
PCM is a phosphorus-containing moiety of Series I, Series Ia, Series Ib; or Series Ic, and m is an integer from 0-3, t is an integer from 1-3, and the sum of m+t is an integer from 1-5.
In still other embodiments RA is hydrogen or lower alkyl and either or both of RB and RD, as described directly above, comprises or is substituted with a phosphorus-containing moiety of Series IIa depicted below: 
wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1); wherein each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 P;
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6;
m is an integer from 0-3; and
PCM is a phosphorus-containing moiety of Series I, Series Ia, Series Ib or Series Ic.
In still other embodiments RA is hydrogen or lower alkyl and either or both of RB and RD, as described directly above, comprises or is substituted with a phosphorus-containing moiety of Series IIb depicted below: 
wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1);
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x;
each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6; and m is an integer from 0-3.
In still other embodiments RA is hydrogen or lower alkyl and either or both of RB and RD, as described directly above, comprises or is substituted with a phosphorus-containing moiety of Series III depicted below: 
wherein each occurrence of R3 is independently hydrogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2; each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x; and m is an integer from 0-4;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6;
each occurrence of R6 is independently hydrogen, aliphatic, heteroaliphatic, aryl or heteroaryl moiety; and
each occurrence of R8 is independently hydrogen, an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or a prodrug moiety; wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.
It will be appreciated that, for each of the classes of compounds described above, in certain embodiments, if q is 0; and RB comprises the only phosphorus-containing moiety PCM and PCM is xe2x80x94P(xe2x95x90O)ORxe2x80x2Rxe2x80x3, or if R9a is xe2x80x94C1-6alkylP(xe2x95x90O)ORxe2x80x2ORxe2x80x3; wherein Rxe2x80x2 and Rxe2x80x3 are independently hydrogen, C1-6alkyl, xe2x80x94(CRxRy)xcfx89xe2x80x94C3-10cycloalkyl or arylC1-6alkyl; wherein w is an integer from 0-5 and Rx and Ry are independently hydrogen or C1-6alkyl; then RB is not phenyl; and
It will also be appreciated that for each of the classes of compounds described above, in certain exemplary embodiments, if q is 0; and RB and RD are each phenyl, then neither RB nor RD is substituted with xe2x80x94P(xe2x95x90O)ORxe2x80x2Rxe2x80x3; and R9a is not xe2x80x94C1-6alkylP(xe2x95x90O)ORxe2x80x2ORxe2x80x3; wherein Rxe2x80x2 and Rxe2x80x3 are independently hydrogen, C1-6alkyl, xe2x80x94(CRxRy)xcfx89xe2x80x94C3-10cycloalkyl or arylC1-6alkyl; wherein w is an integer from 0-5 and Rx and Ry are independently hydrogen or C1-6alkyl.
In certain embodiments, for each of the compounds as described above and herein, Y is a chemical bond linking the phosphorus atom to R1. In certain other embodiments Y is an oxygen atom. In still other embodiments, Y is a chemical bond linking the phosphorus atom to R1 and R1 is a lower alkyl group having 1-6 carbon atoms. In yet other subsets of the compounds as generally described above, RA is hydrogen or an aliphatic or heteroaliphatic moiety and RD is hydrogen. In still other subsets X is oxygen. In yet other embodiments, RE is hydrogen.
In certain embodiments, for each of the compounds as described above and herein, Y is a chemical bond linking the phosphorus atom to R1. In certain other embodiments Y is an oxygen atom. In still other embodiments, Y is a chemical bond linking the phosphorus atom to R1 and R1 is an alkyl group having 1-6 carbon atoms. In yet other subsets of the compounds as generally described above, RA is hydrogen or a lower alkyl moiety. In still other subsets X is oxygen. In yet other embodiments, RE is hydrogen. In still other embodiments K is oxygen.
The following structures illustrate several exemplary types of compounds of the classes and subclasses as described above and herein. Other types will be readily apparent to the reader. 
In addition to the classes of compounds described above, a class of compounds of special interest consists of compounds having the structure of Formula Ia (and pharmaceutically acceptable derivatives thereof): 
wherein AR is an aryl or heteroaryl moiety;
X is oxygen or sulfur;
RA is hydrogen, aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
RB is an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
RC is hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; halogen; cyano; alkyloxycarbonyl; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, and wherein each occurrence of RL and RM is independently hydrogen, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
each occurrence of R9 and R5 is independently hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; cyano; xe2x80x94C(O)RJ; xe2x80x94C(O)ORJ; xe2x80x94NRJC(O)ORK; xe2x80x94OC(O)RJ; xe2x80x94NRJSO2RK; xe2x80x94SO2NRJRK; xe2x80x94NRJC(O)RK; xe2x80x94C(O)NRJRK; xe2x80x94CHxe2x95x90NORJ; xe2x80x94S(O)nRJ, wherein n is an integer from 0 to 2; xe2x80x94(CRLCRM)uxe2x80x94Cxe2x89xa1CRJ; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
R7 is hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; cyano; xe2x80x94C(O)RJ; xe2x80x94C(O)ORJ; xe2x80x94NRJC(O)ORK; xe2x80x94OC(O)RJ; xe2x80x94NRJSO2RK; xe2x80x94SO2NRJRK; xe2x80x94NRJC(O)RK; xe2x80x94C(O)NRJRK; xe2x80x94CHxe2x95x90NORJ; xe2x80x94S(O)nRJ, wherein n is an integer from 0 to 2; xe2x80x94(CRLCRM)uxe2x80x94Cxe2x89xa1CRJ; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
u is an integer from 0-6;
AK is (CRPCRQ);
each occurrence of RP and RQ is independently hydrogen or an aliphatic moiety; each occurrence of n is independently 0-3;
q is an integer from 0 to 5;
p is an integer from 0-3;
r is an integer from 0-2;
R9a is hydrogen; or an aliphatic or heteroaliphatic moiety;
each occurrence of PCM is independently a phosphorus-containing moiety;
t is an integer from 1-3;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted; and
RB optionally additionally comprises a phosphorus-containing moiety.
Another class of compounds of interest include those compounds of the structure of Formula Ib (and pharmaceutically acceptable derivatives thereof): 
wherein AR is an aryl or heteroaryl moiety;
X is oxygen or sulfur;
RA is hydrogen, aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
RC is hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; halogen; cyano; alkyloxycarbonyl; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, and wherein each occurrence of RL and RM is independently hydrogen, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
RD is an aryl or heteroaryl moiety;
each occurrence of R9 and R5 is independently hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; cyano; xe2x80x94C(O)RJ; xe2x80x94C(O)ORJ; xe2x80x94NRJC(O)ORK; xe2x80x94OC(O)RJ; xe2x80x94NRJSO2RK; xe2x80x94SO2NRJRK; xe2x80x94NRJC(O)RK; xe2x80x94C(O)NRJRK; xe2x80x94CHxe2x95x90NORJ; xe2x80x94S(O)nRJ, wherein n is an integer from 0 to 2; xe2x80x94(CRLCRM)uxe2x80x94Cxe2x89xa1CRJ; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
R7 is hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; cyano; xe2x80x94C(O)RJ; xe2x80x94C(O)ORJ; xe2x80x94NRJC(O)ORK; xe2x80x94OC(O)RJ; xe2x80x94NRJSO2RK; xe2x80x94SO2NRJRK; xe2x80x94NRJC(O)RK; xe2x80x94C(O)NJRK; xe2x80x94CHxe2x95x90NORJ; xe2x80x94S(O)nRJ, wherein n is an integer from 0 to 2; xe2x80x94(CRLCRM)uxe2x80x94Cxe2x89xa1CRJ; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
u is an integer from 0-6;
AK is (CRPCRQ);
each occurrence of RP and RQ is independently hydrogen or an aliphatic moiety; each occurrence of n is independently 0-3;
q is an integer from 0 to 5;
p is an integer from 0-3;
r is an integer from 0-2;
R9a is hydrogen; or an aliphatic or heteroaliphatic moiety;
each occurrence of PCM is independently a phosphorus-containing moiety;
t is an integer from 1-3;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted; and
RD optionally additionally comprises a phosphorus-containing moiety.
Another class of compounds of interest include those compounds of the structure of Formula Ic (and pharmaceutically acceptable derivatives thereof): 
wherein each occurrence of AR is independently an aryl or heteroaryl moiety;
X is oxygen or sulfur;
RA is hydrogen, aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
RC is hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; halogen; cyano; alkyloxycarbonyl; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, and wherein each occurrence of RL and RM is independently hydrogen, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
each occurrence of R9 and R5 is independently hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; cyano; xe2x80x94C(O)RJ; xe2x80x94C(O)ORJ; xe2x80x94NRJC(O)ORK; xe2x80x94OC(O)RJ; xe2x80x94NRJSO2RK; xe2x80x94SO2NRJRK; xe2x80x94NRJC(O)RK; xe2x80x94C(O)NRJRK; xe2x80x94CHxe2x95x90NORJ; xe2x80x94S(O)nRJ, wherein n is an integer from 0 to 2; xe2x80x94(CRJCRM)uxe2x80x94Cxe2x89xa1CRJ; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
R7 is hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; cyano; xe2x80x94C(O)RJ; xe2x80x94C(O)ORJ; xe2x80x94NRJC(O)ORK; xe2x80x94OC(O)RJ; xe2x80x94NRJSO2RK; xe2x80x94SO2NRJRK; xe2x80x94NRJC(O)RK; xe2x80x94C(O)NRJRK; xe2x80x94CHxe2x95x90NORJ; xe2x80x94S(O)nRJ, wherein n is an integer from 0 to 2; xe2x80x94(CRLCRM)uxe2x80x94Cxe2x89xa1CRJ; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
u is an integer from 0-6;
AK is (CRPCRQ);
each occurrence of RP and RQ is independently hydrogen or an aliphatic moiety; each occurrence of n is independently 0-3;
q is an integer from 0 to 5;
p is an integer from 0-3;
r is an integer from 0-2;
R9a is hydrogen; or an aliphatic or heteroaliphatic moiety;
PCM, for each occurrence, is independently a phosphorus-containing moiety;
t and txe2x80x2 are each independently an integer from 0-3; wherein the sum t+txe2x80x2 is at least 1;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.
In certain other subsets of interest for compounds as described in Formulas Ia-Ic above, AR is an aryl or heteroaryl moiety selected from phenyl, pyridyl, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole and pyrimidine, optionally further substituted with one or more occurrences of R3, as defined herein.
A subclass of special interest of compounds of Formula Ia described above, consists of compounds having the structure of Formula Id (and pharmaceutically acceptable derivatives thereof) in which AR is a phenyl moiety substituted with a phosphorus-containing moiety: 
X is oxygen or sulfur;
RA is hydrogen, aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
RB is an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
RC is hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; halogen; cyano; alkyloxycarbonyl; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, and wherein each occurrence of RL and RM is independently hydrogen, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
each occurrence of R9 and R5 is independently hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; cyano; xe2x80x94C(O)RJ; xe2x80x94C(O)ORJ; xe2x80x94NRJC(O)ORK; xe2x80x94OC(O)RJ; xe2x80x94NRJSO2RK; xe2x80x94SO2NRJRK; xe2x80x94NRJC(O)RK; xe2x80x94C(O)NRJRK; xe2x80x94CHxe2x95x90NORJ; xe2x80x94S(O)nRJ, wherein n is an integer from 0 to 2; xe2x80x94(CRLCRM)uxe2x80x94Cxe2x89xa1CRJ; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
R7 is hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; cyano; xe2x80x94C(O)RJ; xe2x80x94C(O)ORJ; xe2x80x94NRJC(O)ORK; xe2x80x94OC(O)RJ; xe2x80x94NRJSO2RK; xe2x80x94SO2NRJRK; xe2x80x94NRJC(O)RK; xe2x80x94C(O)NRJRK; xe2x80x94CHxe2x95x90NORJ; xe2x80x94S(O)nRJ, wherein n is an integer from 0 to 2; xe2x80x94(CRLCRM)uxe2x80x94Cxe2x89xa1CRJ; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
u is an integer from 0-6;
AK is (CRPCRQ);
each occurrence of RP and RQ is independently hydrogen or an aliphatic moiety; each occurrence of n is independently 0-3;
q is an integer from 0 to 5;
p is an integer from 0-3;
r is an integer from 0-2;
R9a is hydrogen; or an aliphatic or heteroaliphatic moiety;
each occurrence of R3 is independently hydrogen; halogen; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, or sulfonamido; wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2; each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H; each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94 or (M)x; each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated; and each occurrence of x is independently an integer from 0-6;
s is an integer from 0-3;
each occurrence of PCM is independently a phosphorus-containing moiety;
t is an integer from 1-3;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted; and
RB optionally additionally comprises a phosphorus-containing moiety.
A subclass of special interest of compounds of Formula Ib described above, consists of compounds having the structure of Formula Ie (and pharmaceutically acceptable derivatives thereof) in which AR is a phenyl moiety substituted with a phosphorus-containing moiety: 
wherein X is oxygen or sulfur;
RA is hydrogen, aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
RC is hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; halogen; cyano; alkyloxycarbonyl; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, and wherein each occurrence of RLand RM is independently hydrogen, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
each occurrence of R9 and R5 is independently hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; cyano; xe2x80x94C(O)RJ; xe2x80x94C(O)ORJ; xe2x80x94NRJC(O)ORK; xe2x80x94OC(O)RJ; xe2x80x94NRJSO2RK; xe2x80x94SO2NRJRK; xe2x80x94NRJC(O)RK; xe2x80x94C(O)NRJRK; xe2x80x94CHxe2x95x90NORJ; xe2x80x94S(O)nRJ, wherein n is an integer from 0 to 2; xe2x80x94(CRLCRM)uxe2x80x94Cxe2x89xa1CRJ; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
R7 is hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; cyano; xe2x80x94C(O)RJ; xe2x80x94C(O)ORJ; xe2x80x94NRJC(O)ORK; xe2x80x94OC(O)RJ; xe2x80x94NRJSO2R ; xe2x80x94SO2NRJRK; xe2x80x94NRJC(O)RK; xe2x80x94C(O)NRJRK; xe2x80x94CHxe2x95x90NORJ; xe2x80x94S(O)nRJ, wherein n is an integer from 0 to 2; xe2x80x94(CRLCRM)uxe2x80x94Cxe2x89xa1CRJ; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
u is an integer from 0-6;
AK is (CRPCRQ);
each occurrence of RP and RQ is independently hydrogen or an aliphatic moiety; each occurrence of n is independently 0-3;
q is an integer from 0 to 5;
p is an integer from 0-3;
r is an integer from 0-2;
R9a is hydrogen; or an aliphatic or heteroaliphatic moiety;
each occurrence of R3 is independently hydrogen; halogen; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, or sulfonamido; wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2; each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H; each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94 or (M)x; each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated; and each occurrence of x is independently an integer from 0-6;
s is an integer from 0-3;
PCM is a phosphorus-containing moiety;
t is an integer from 1-3;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted; and
RD optionally additionally comprises a phosphorus-containing moiety.
A subclass of special interest of compounds of Formula Ic described above, consists of compounds having the structure of Formula If (and pharmaceutically acceptable derivatives thereof) in which each AR moiety is independently a phenyl moiety substituted with a phosphorus-containing moiety: 
wherein X is oxygen or sulfur;
RA is hydrogen, aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
RC is hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; halogen; cyano; alkyloxycarbonyl; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, and wherein each occurrence of RL and RM is independently hydrogen, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
each occurrence of R9 and R5 is independently hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; cyano; xe2x80x94C(O)RJ; xe2x80x94C(O)ORJ; xe2x80x94NRJC(O)ORK; xe2x80x94OC(O)RJ; xe2x80x94NRJSO2RK; xe2x80x94SO2NRJRK; xe2x80x94NRJC(O)RK; xe2x80x94C(O)NRJRK; xe2x80x94CHxe2x95x90NORJ; xe2x80x94S(O)nRJ, wherein n is an integer from 0 to 2; xe2x80x94(CRLCRM)uxe2x80x94Cxe2x89xa1CRJ; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
R7 is hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; cyano; xe2x80x94C(O)RJ; xe2x80x94C(O)ORJ; xe2x80x94NRJC(O)ORK; xe2x80x94OC(O)RJ; xe2x80x94NRJSO2RK; xe2x80x94SO2NRJRK; xe2x80x94NRJC(O)RK; xe2x80x94C(O)NRJRK; xe2x80x94CHxe2x95x90NORJ; xe2x80x94S(O)nRJ, wherein n is an integer from 0 to 2; xe2x80x94(CRLCRM)uxe2x80x94Cxe2x89xa1CRJ; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
u is an integer from 0-6;
AK is (CRPCRQ);
each occurrence of RP and RQ is independently hydrogen or an aliphatic moiety; each occurrence of n is independently 0-3;
q is an integer from 0 to 5;
p is an integer from 0-3;
r is an integer from 0-2;
R9a is hydrogen; or an aliphatic or heteroaliphatic moiety;
each occurrence of R3 is independently hydrogen; halogen; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, or sulfonamido; wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2; each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H; each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94 or (M)x; each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated; and each occurrence of x is independently an integer from 0-6;
each occurrence of s is independently an integer from 0-3;
each occurrence of PCM is independently a phosphorus-containing moiety;
t and txe2x80x2 are each independently an integer from 0-3; wherein the sum t+txe2x80x2 is at least 1;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.
In certain subsets of interest for Formulas Ia and Id, as described above, and other subsets of interest as described herein, RB is an aryl or heteroaryl moiety substituted independently with one or more occurrences of hydrogen, halogen, cyano, hydroxy, or alkoxy. In other subsets each occurrence of R9 and R5 are each hydrogen. In still other subsets R7 is NH2 or N(alkyl)2. In still other subsets RA is hydrogen or an aliphatic moiety. In yet other subsets RA is hydrogen or a C1-6 linear alkyl moiety or is a C5 or C6 cyclic alkyl moiety. In still other subsets of compounds as described above and herein, R9a is hydrogen or an aliphatic or heteroaliphatic moiety. In certain other subsets R9a is hydrogen or a C1-6 alkyl or heteroalkyl moiety. In yet other subsets of interest R9a is hydrogen, methyl or ethyl.
In certain other subsets of interest for Formulas Ib and Ie, as described above, and other subsets of interest as described herein RD is an aryl or heteroaryl moiety substituted independently with one or more occurrences of hydrogen, halogen, cyano, hydroxy, or alkoxy. In other subsets each occurrence of R9 and R5 are each hydrogen. In still other subsets R7 is xe2x80x94NH2, xe2x80x94OH, xe2x80x94N(alkyl)2 or xe2x80x94Oalkyl. In still other subsets RA is an aliphatic moiety. In yet other subsets RA is a C1-6 linear alkyl moiety or is a C5 or C6 cyclic alkyl moiety. In still other subsets of compounds as described above and herein, R9a is an aliphatic or heteroaliphatic moiety. In certain other subsets R9a is a C1-6 alkyl or heteroalkyl moiety. In yet other subsets of interest R9a is hydrogen, methyl or ethyl.
In certain other subsets of interest for Formulas Ic and If, as described above, and other subsets of interest as described herein, each phenyl moiety is substituted independently with one or more occurrences of hydrogen, halogen, cyano, hydroxy, or alkoxy. In other subsets each occurrence of R9 and R5 are each hydrogen. In still other subsets R7 is xe2x80x94NH2, xe2x80x94OH, xe2x80x94N(alkyl)2 or xe2x80x94Oalkyl. In still other subsets RA is an aliphatic moiety. In yet other subsets RA is a C1-6 linear alkyl moiety or is a C5 or C6 cyclic alkyl moiety. In still other subsets of compounds as described above and herein, R9a is an aliphatic or heteroaliphatic moiety. In certain other subsets R9a is a C1-6 alkyl or heteroalkyl moiety. In yet other subsets of interest R9a is hydrogen, methyl or ethyl. In still other subsets, if RB (or specific substituents, e.g., AR, phenyl, as further defined for RB) is a phenyl moiety where t is 0 and thus RB does not comprise a phosphorus-containing moiety, then one or more occurrences of R3 is OH, alkoxy, or halogen. In yet other subsets if RD (or specific substituents, e.g, AR, phenyl, as further defined for RD) is a phenyl moiety where txe2x80x2 is 0 and thus RD does not comprise a phosphorus-containing moiety, then one or more occurrences of R3 is OH, alkoxy, or halogen.
In yet another subset of compounds of particular interest, X is oxygen, R7 is NH2 and the compound has the structure of Formula Ig (and pharmaceutically acceptable derivatives thereof): 
wherein is hydrogen, aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
RB is an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
RC is hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; halogen; cyano; alkyloxycarbonyl; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, and wherein each occurrence of RL and RM is independently hydrogen, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
RD is an aryl or heteroaryl moiety;
each occurrence of R9 and R5 is independently hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; cyano; xe2x80x94C(O)RJ; xe2x80x94C(O)ORJ; xe2x80x94NRJC(O)ORK; xe2x80x94OC(O)RJ; xe2x80x94NRJSO2RK; xe2x80x94SO2NRJRK; xe2x80x94NRJC(O)RK; xe2x80x94C(O)NRJRK; xe2x80x94CHxe2x95x90NORJ; xe2x80x94S(O)nRJ, wherein n is an integer from 0 to 2; xe2x80x94(CRLCRM)uCxe2x89xa1CRJ; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
R7 is hydrogen; aliphatic; heteroaliphatic; aryl; heteroaryl; cyano; xe2x80x94C(O)RJ; xe2x80x94C(O)ORJ; xe2x80x94NRJC(O)ORK; xe2x80x94OC(O)RJ; xe2x80x94NRJSO2RK; xe2x80x94SO2NRJRK; xe2x80x94NRJC(O)RK; xe2x80x94C(O)NRJRK; xe2x80x94CHxe2x95x90NORJ; xe2x80x94S(O)nRJ, wherein n is an integer from 0 to 2; xe2x80x94(CRLCRM)uxe2x80x94Cxe2x89xa1CRJ; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94CO(NORL)RM, xe2x80x94CHxe2x95x90NORJ, xe2x80x94NRLRM, xe2x80x94S(O)2RL, xe2x80x94P(O)(ORL)RM, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
u is an integer from 0-6;
AK is (CRPCRQ);
each occurrence of RP and RQ is independently hydrogen or an aliphatic moiety;
q is an integer from 0 to 5;
p is an integer from 0-3;
r is an integer from 0-2;
R9a is hydrogen; or an aliphatic or heteroaliphatic moiety;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted; and
at least one of RB or RD as defined above, comprises a phosphorus-containing moiety.
In certain embodiments for Formulas Ia-Ig, as described above, one or both of RB or RD (or specific substituents, e.g., AR, phenyl, as further defined for RB and RD) comprises or is substituted with a phosphorus-containing moiety of Series I: 
wherein each occurrence of K is independently O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1);
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94 or (M)x;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6; and
each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted.
In certain other embodiments, the phosphorus-containing moiety of Formulas Ia-Ig is selected from Series Ia or Ib below: 
wherein each occurrence of K is independently O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl, alkylaryl, or alkylheteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1);
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94 or (M)x;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6; and
each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted; and each occurrence of R4 is independently an aliphatic, heteroaliphatic, aryl or heteroaryl moiety. In certain embodiments, M is xe2x80x94CRxRy, wherein each occurrence of Rx and Ry is independently hydrogen, halogen, alkyl, heteroalkyl, ORL or NRLRM; wherein each occurrence of RL and RM is independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety. In certain exemplary embodiments, M is xe2x80x94CH2xe2x80x94, xe2x80x94CH(OH)xe2x80x94, xe2x80x94CH(NH2)xe2x80x94, xe2x80x94C(alkyl)(OH)xe2x80x94, xe2x80x94C(alkyl)(NH2)xe2x80x94, xe2x80x94CH(halo)- or xe2x80x94C(halo)2-.
In certain other embodiments, the phosphorus-containing moiety of Formulas Ia-Ig is selected from Series Ic depicted below: 
wherein each occurrence of R1 is independently hydrogen, alkyl or aryl;
each occurrence of R4 is independently alkyl or aryl;
each occurrence of R6 is independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; and
each occurrence of R8 is independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, or a prodrug moiety.
In certain embodiments, R6 is hydrogen, lower alkyl, ORL or NRLRM; wherein each occurrence of RL and RM is independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety. In certain other embodiments, R6 is hydrogen, methyl, ethyl, OH or NH2. In certain embodiments, R8 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl or a prodrug moiety. In still other embodiments, R8 is hydrogen, methyl, ethyl, or a prodrug moiety.
In certain other embodiments, for each of the foregoing classes of Formulas Ib-If as described above, either or both of RB or RD (or specific substituents as further defined for RB and RD, e.g., AR, phenyl) comprises or is substituted with any one of the phosphorus-containing aryl of heteroaryl moieties of Series II: 
wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2; and each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6;
PCM is a phosphorus-containing moiety of Series I, Series Ia, Series Ib; or Series Ic, and m is an integer from 0-3, t is an integer from 1-3, and the sum of m+t is an integer from 1-5.
In still other embodiments, for each of the foregoing classes of Formulas Ib-If as described above, either or both of RB or RD (or specific substituents as further defined for RB and RD, e.g., AR, phenyl) comprises any one of the phosphorus-containing aryl of heteroaryl moieties of Series IIa: 
wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1); wherein each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6;
m is an integer from 0-3; and
PCM is a phosphorus-containing moiety of Series I, Series Ia, Series Ib or Series Ic.
In certain exemplary embodiments, PCM is independently, for each occurrence, a phosphorus-containing moiety of Series Ic depicted below: 
wherein each occurrence of R1 is independently hydrogen, alkyl or aryl;
each occurrence of R4 is independently alkyl or aryl;
each occurrence of R6 is independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; and
each occurrence of R8 is independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, or a prodrug moiety.
In certain embodiments, R6 is hydrogen, lower alkyl, ORL or NRLRM; wherein each occurrence of RL and RM is independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety. In certain other embodiments, R6 is hydrogen, methyl, ethyl, OH or NH2. In certain embodiments, R8 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl or a prodrug moiety. In still other embodiments, R8 is hydrogen, methyl, ethyl, or a prodrug moiety.
In still other embodiments, for each of the foregoing classes of Formulas Ib-If as described above, either or both of RB or RD (or specific substituents as further defined for RB and RD, e.g, AR, phenyl) comprises any one of the phosphorus-containing aryl of heteroaryl moieties of Series IIb: 
wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94(O)(YR1);
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x;
each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6; and
m is an integer from 0-3.
In still other embodiments, for each of the foregoing classes of Formulas Ib-If as described above, either or both of RB or RD (or specific substituents as further defined for RB and RD, e.g., AR, phenyl) comprises any one of the phosphorus-containing aryl of heteroaryl moieties of Series III: 
wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2; each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x; and m is an integer from 0-4;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6;
each occurrence of R6 is independently hydrogen, aliphatic, heteroaliphatic, aryl or heteroaryl moiety; and
each occurrence of R8 is independently hydrogen, an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or a prodrug moiety; wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.
It will be appreciated that, in certain exemplary embodiments, for each of the foregoing classes of Formulas Ib-If as described above, both RB and RD (or specific substituents as further defined for RB and RD, e.g., AR, phenyl) independently comprises or is substituted with a phosphorus-containing moiety of Series I, Ia, Ib, Ic, II, IIa or IIb. In certain other embodiments, either or both RB and RD comprises or is substituted with a phosphorus-containing moiety of Series I as depicted below: 
wherein each occurrence of K is independently O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1);
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94 or (M)x;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6; and
each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted.
It will be appreciated that in certain exemplary embodiments, both RB and RD as a described directly above, comprises or is substituted with at least one of the phosphorus-containing moieties in Series Ic depicted below: 
wherein each occurrence of R1 is independently hydrogen, alkyl or aryl;
each occurrence of R4 is independently alkyl or aryl;
each occurrence of R6 is independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; end
each occurrence of R8 is independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, or a prodrug moiety.
In certain embodiments, R6 is hydrogen, lower alkyl, ORL or NRLRM; wherein each occurrence of RL and RM is independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety. In certain other embodiments, R6 is hydrogen, methyl, ethyl, OH or NH2. In certain embodiments, R8 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl or a prodrug moiety. In still other embodiments, R8 is hydrogen, methyl, ethyl, or a prodrug moiety.
In certain embodiments, for each of the compounds as described above and herein, Y is a chemical bond linking the phosphorus atom to R1. In certain other embodiments Y is an oxygen atom. In still other embodiments, Y is a chemical bond linking the phosphorus atom to R1 and R1 is an alkyl group having 1-6 carbon atoms. In yet other subsets of the compounds as generally described above, RA is hydrogen or an aliphatic or heteroaliphatic moiety.
In certain embodiments, for each of the compounds as described above and herein, M is xe2x80x94CRxRy, wherein each occurrence of Rx and Ry is independently hydrogen, halogen, alkyl, heteroalkyl, ORL or NRLRM; wherein each occurrence of RL and RM is independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety. In certain exemplary embodiments, x is 1 and M is xe2x80x94CH2xe2x80x94, xe2x80x94CH(OH)xe2x80x94, xe2x80x94CH(NH2)xe2x80x94, xe2x80x94C(alkyl)(OH)xe2x80x94, xe2x80x94C(alkyl)(NH2)xe2x80x94, xe2x80x94CH(halo)- or xe2x80x94C(halo)2-.
A number of important subclasses of the foregoing classes of compounds deserve separate mention. Those subclasses include subclasses of the foregoing classes in which:
i) Y is a chemical bond linking the phosphorus atom to R1;
ii) Y is an oxygen atom;
iii) Y is an oxygen atom and R1 is H;
iv) Y is a chemical bond linking the phosphorus atom to R1, and R1 is an alkyl group having 1-6 carbon atoms;
v) R1 is a lower alkyl moiety;
vi) K is oxygen;
vii) X is oxygen;
viii) RA is hydrogen, oxygen or a lower alkyl moiety;
xix) RA is hydrogen;
x) RA is methyl, ethyl or propyl;
xi) RA is methyl
xii) AR, RB or RD comprises an aryl or heteroaryl moiety selected from phenyl, pyridyl, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole and pyrimidine; wherein each of the aryl or heteroaryl moieties is optionally substituted with one or more phosphorus-containing moieties, PCM, from Series I, Ia, Ib or Ic, and is optionally further substituted with one or more occurrences of R3;
xiii) at least one of AR, RB or RD comprises a phosphorus-containing aryl or heteroaryl moiety from Series II, IIa or III, and is optionally further substituted with one or more occurrences of R3;
xiv) RB is a substituted or unsubstituted phenyl moiety; optionally substituted with one or more phosphorus-containing moieties, PCM, from Series I, Ia, Ib or Ic, and is optionally further substituted with one or more occurrences of R3;
xv) RB is a substituted or unsubstituted pyridinyl moiety; optionally substituted with one or more phosphorus-containing moieties, PCM, from Series I, Ia, Ib or Ic, and is optionally further substituted with one or more occurrences of R3;
xvi) RD is a substituted or unsubstituted phenyl moiety; optionally substituted with one or more phosphorus-containing moieties, PCM, from Series I, Ia, Ib or Ic, and is optionally further substituted with one or more occurrences of R3;
xvii) RD is a substituted or unsubstituted pyridinyl moiety; optionally substituted with one or more phosphorus-containing moieties, PCM, from Series I, Ia, Ib or Ic, and is optionally further substituted with one or more occurrences of R3;
xviii) wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2; wherein R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H; and each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x;
xix) each occurrence of R3 is independently halogen, hydroxyl, amino, or is an aliphatic or heteroaliphatic moiety, wherein the aliphatic or heteroaliphatic moiety is substituted or unsubstituted, cyclic or acyclic, linear or branched;
xx) one or more occurrences of R3 is lower alkyl, halo, or lower alkoxy;
xxi) r is 1 and R3 is halogen;
xxii) r is 1 and R3 is chlorine;
xxiii) r is 1 and R3 is chlorine located at the ortho position;
xxiv) r is 1 and R3 is chlorine located at the meta position;
xxv)) either or both of RB and RD independently comprises or is substituted with a phosphorus-containing moiety of Series I, Ia, Ib, Ic, II, IIa, IIb or III;
xxvi)) both RB and RD independently comprise or are substituted with a phosphorus-containing moiety of Series I, Ia, Ib, Ic, II, IIa, IIb or III;
xxvii) RC is hydrogen or lower alkyl;
xxviii) RC is hydrogen;
xxix) R7 is hydrogen, OH, alkoxy or NH2;
xxx) R7 is NH2;
xxxi) RC is hydrogen and R7 is NH2;
xxxii) R9a is hydrogen or or a Cl1-6 alkyl or heteroalkyl moiety;
xxxiii) R9a is hydrogen or lower alkyl;
xxxiv) R9a is hydrogen, methyl or ethyl;
xxxv) R9 is hydrogen, halogen or lower alkyl;
xxxvi) R5 is hydrogen, halogen or lower alkyl;
xxxvii) R9 and R5 are each hydrogen;
xxxviii) q is 0;
xxxix) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein each R1 is independently H, alkyl, arylalkyl, aryl or a prodrug moiety;
xl) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein each R1 is independently H, alkyl, arylalkyl, aryl or a prodrug moiety;
xli) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein each R1 is independently H, alkyl, arylalkyl, aryl or a prodrug moiety; and M is xe2x80x94CH2xe2x80x94, xe2x80x94CH(OH)xe2x80x94, xe2x80x94CH(NH2)xe2x80x94, xe2x80x94C(alkyl)(OH)xe2x80x94, xe2x80x94C(alkyl)(NH2)xe2x80x94, xe2x80x94CH(halo)- or xe2x80x94C(halo)2-;
xlii) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein each R1 is independently H, alkyl, arylalkyl, aryl or a prodrug moiety;
xliii) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein each R4 is independently alkyl, arylalkyl, aryl or a prodrug moiety;
xliv) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein R1 is H, alkyl, arylalkyl or a prodrug moiety and R4 is alkyl, arylalkyl, aryl or a prodrug moiety;
xlv) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein each R4 is independently alkyl, arylalkyl, aryl or a prodrug moiety;
xlvi) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein each R1 is independently H, alkyl, arylalkyl or a prodrug moiety, and Y and M are as defined previously;
xlvii) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein each R1 is independently H, alkyl, arylalkyl or a prodrug moiety, and Y is as defined previously; and M is xe2x80x94CH2xe2x80x94, xe2x80x94CH(OH)xe2x80x94, xe2x80x94CH(NH2)xe2x80x94, xe2x80x94C(alkyl)(OH)xe2x80x94, xe2x80x94C(alkyl)(NH2)xe2x80x94, xe2x80x94CH(halo)- or xe2x80x94C(halo)2-;
xlviii) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein each R1 is independently H, alkyl, arylalkyl, aryl or a prodrug moiety;
xlix) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein each R1 is independently H, alkyl, arylalkyl, aryl or a prodrug moiety, and Y is as defined previously;
l) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein each R1 is independently H, alkyl, arylalkyl or a prodrug moiety, and R6 is hydrogen, lower alkyl, ORL or NRLRM; wherein each occurrence of RL and RM is independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety;
li) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein each R1 is independently H, alkyl, arylalkyl or a prodrug moiety, and R6 is hydrogen, lower alkyl, ORL or NRLRM; wherein each occurrence of RL and RM is independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety;
lii) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein R1 is H, alkyl, arylalkyl or a prodrug moiety, and R6 is as previously defined;
liii) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein each R1 is independently H, alkyl, arylalkyl or a prodrug moiety, R6 is as previously defined, and R8 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl or a prodrug moiety;
liv) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein each R1 is independently H, alkyl, arylalkyl or a prodrug moiety, and R6 and R8 are as previously defined;
lv) RB or RD (and substituents defined therein) independently comprises or is substituted with: 
wherein each occurrence of R1 is independently H, alkyl, arylalkyl or a prodrug moiety, and R6 and R8 are as previously defined;
lvi) if q is 0; and RB comprises the only phosphorus-containing moiety PCM and PCM is xe2x80x94P(xe2x95x90O)ORxe2x80x2Rxe2x80x3, or if R9a is xe2x80x94C1-6alkylP(xe2x95x90O)ORxe2x80x2ORxe2x80x3; wherein Rxe2x80x2 and Rxe2x80x3 are independently hydrogen, C1-6alkyl, xe2x80x94(CRxRy)xcfx89xe2x80x94C3-10cycloalkyl or arylC1-6alkyl; wherein w is an integer from 0-5 and Rx and Ry are independently hydrogen or C1-6alkyl; then RB is not phenyl; and
lvii) if q is 0; and RB and RD are each phenyl, then neither RB nor RD is substituted with xe2x80x94P(xe2x95x90O)ORxe2x80x2Rxe2x80x3; and R9a is not xe2x80x94C1-6alkylP(xe2x95x90O)ORxe2x80x2ORxe2x80x3; wherein Rxe2x80x2 and Rxe2x80x3 are independently hydrogen, C1-6alkyl, xe2x80x94(CRxRy)xcfx89xe2x80x94C3-10cycloalkyl or arylC1-6alkyl; wherein w is an integer from 0-5 and Rx and Ry are independently hydrogen or C1-6alkyl.
As the reader will appreciate, compounds of particular interest include, among others, those that share the attributes of one or more of the foregoing subclasses.
Some of those subclasses are illustrated by the following sorts of compounds:
I. Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof): 
wherein AR is an aryl or heteroaryl moiety;
RA is hydrogen, oxygen, or an alkyl or heteroalkyl moiety;
RB is an alkyl, heteroalkyl, aryl or heteroaryl moiety;
RC is hydrogen; halogen, cyano or an alkyl or heteroalkyl moiety;
each occurrence of R9 and R5 is independently hydrogen, halogen, alkyl or heteroalkyl;
R7 is hydrogen; alkyl; heteroalkyl; aryl; heteroaryl; cyano; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94NRLRM, or an alkyl, heteroalkyl, aryl or heteroaryl moiety;
AK is (CRPCRQ);
each occurrence of RP and RQ is independently hydrogen or an alkyl or heteroalkyl moiety;
q is an integer from 0 to 5;
p is an integer from 0-3;
r is an integer from 0-2;
R9a is hydrogen; or an alkyl or heteroalkyl moiety;
K is O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NR1xe2x80x94, or a chemical bond linking R1 to P,
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
x is 0-6;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted; and
RB optionally additionally comprises or is substituted with a phosphorus-containing moiety.
In certain embodiments, RB is an aryl or heteroaryl moiety substituted independently with one or more occurrences of hydrogen, halogen, cyano, hydroxy, or alkoxy. In certain other embodiments each occurrence of R9 and R5 are each hydrogen. In still other embodiments R7 is NH2 or N(alkyl)2. In still other exemplary embodiments RA is hydrogen or methyl. In yet other embodiments of interest R9a is hydrogen, methyl or ethyl. In certain other embodiments, q is 0.
II. Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof): 
wherein AR is an aryl or heteroaryl moiety;
RA is hydrogen, oxygen, or an alkyl or heteroalkyl moiety;
RC is hydrogen; halogen, cyano or an alkyl or heteroalkyl moiety;
RD is an alkyl, heteroalkyl, aryl or heteroaryl moiety;
each occurrence of R9 and R5 is independently hydrogen, halogen, alkyl or heteroalkyl;
R7 is hydrogen; alkyl; heteroalkyl; aryl; heteroaryl; cyano; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94NRLRM, or an alkyl, heteroalkyl, aryl or heteroaryl moiety;
AK is (CRPCRQ);
each occurrence of RP and RQ is independently hydrogen or an alkyl or heteroalkyl moiety;
q is an integer from 0 to 5;
p is an integer from 0-3;
r is an integer from 0-2;
R9a is hydrogen; or an alkyl or heteroalkyl moiety;
K is O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NR1xe2x80x94, or a chemical bond linking R1 to P, each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
x is 0-6;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted; and
RD optionally additionally comprises or is substituted with a phosphorus-containing moiety.
In certain embodiments, RD is an aryl or heteroaryl moiety substituted independently with one or more occurrences of hydrogen, halogen, cyano, hydroxy, or alkoxy. In certain other embodiments each occurrence of R9 and R5 are each hydrogen. In still other embodiments R7 is NH2 or N(alkyl)2. In still other exemplary embodiments RA is hydrogen or methyl. In yet other embodiments of interest R9a is hydrogen, methyl or ethyl. In certain other embodiments, q is 0.
III. Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof): 
wherein each occurrence of AR is independently an aryl or heteroaryl moiety;
RA is hydrogen, oxygen, or an alkyl or heteroalkyl moiety;
RC is hydrogen; halogen, cyano or an alkyl or heteroalkyl moiety;
each occurrence of R9 and R5 is independently hydrogen, halogen, alkyl or heteroalkyl;
R7 is hydrogen; alkyl; heteroalkyl; aryl; heteroaryl; cyano; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94NRLRM, or an alkyl, heteroalkyl, aryl or heteroaryl moiety;
AK is (CRPCRQ);
each occurrence of RP and RQ is independently hydrogen or an alkyl or heteroalkyl moiety;
q is an integer from 0 to 5;
p is an integer from 0-3;
r is an integer from 0-2;
R9a is hydrogen; or an alkyl or heteroalkyl moiety;
K is O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NR1xe2x80x94, or a chemical bond linking R1 to P,
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
x is 0-6;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.
In certain embodiments, R9 and R5 are each hydrogen. In still other embodiments R7 is NH2 or N(alkyl)2. In still other exemplary embodiments RA is hydrogen or methyl. In yet other embodiments of interest R9a is hydrogen, methyl or ethyl. In certain other embodiments, q is 0.
IV. Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof): 
wherein RA is hydrogen, oxygen, or an alkyl or heteroalkyl moiety;
RB is an alkyl, heteroalkyl, aryl or heteroaryl moiety;
RC is hydrogen; halogen, cyano or an alkyl or heteroalkyl moiety;
each occurrence of R9 and R5 is independently hydrogen, halogen, alkyl or heteroalkyl;
R7 is hydrogen; alkyl; heteroalkyl; aryl; heteroaryl; cyano; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94NRLRM, or an alkyl, heteroalkyl, aryl or heteroaryl moiety;
AK is (CRPCRQ);
each occurrence of RP and RQ is independently hydrogen or an alkyl or heteroalkyl moiety;
q is an integer from 0 to 5;
p is an integer from 0-3;
r is an integer from 0-2;
R9a is hydrogen; or an alkyl or heteroalkyl moiety;
K is O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NR1xe2x80x94, or a chemical bond linking R1 to P,
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
x is 0-6;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted; and
RB optionally additionally comprises or is substituted with a phosphorus-containing moiety.
In certain embodiments, RB is an aryl or heteroaryl moiety substituted independently with one or more occurrences of hydrogen, halogen, cyano, hydroxy, or alkoxy. In certain other embodiments each occurrence of R9 and R5 are each hydrogen. In still other embodiments R7 is NH2 or N(alkyl)2. In still other exemplary embodiments RA is hydrogen or methyl. In yet other embodiments of interest R9a is hydrogen, methyl or ethyl. In certain other embodiments, q is 0.
V Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof): 
wherein RA is hydrogen, oxygen, or an alkyl or heteroalkyl moiety;
RC is hydrogen; halogen, cyano or an alkyl or heteroalkyl moiety;
RD is an alkyl, heteroalkyl, aryl or heteroaryl moiety;
each occurrence of R9 and R5 is independently hydrogen, halogen, alkyl or heteroalkyl;
R7 is hydrogen; alkyl; heteroalkyl; aryl; heteroaryl; cyano; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94NRLRM, or an alkyl, heteroalkyl, aryl or heteroaryl moiety;
AK is (CRPCRQ);
each occurrence of RP and RQ is independently hydrogen or an alkyl or heteroalkyl moiety;
q is an integer from 0 to 5;
p is an integer from 0-3;
r is an integer from 0-2;
R9a is hydrogen; or an alkyl or heteroalkyl moiety;
K is O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NR1xe2x80x94, or a chemical bond linking R1 to P, each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
x is 0-6;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted; and
RD optionally additionally comprises or is substituted with a phosphorus-containing moiety.
In certain embodiments, RD is an aryl or heteroaryl moiety substituted independently with one or more occurrences of hydrogen, halogen, cyano, hydroxy, or alkoxy. In certain other embodiments each occurrence of R9 and R5 are each hydrogen. In still other embodiments R7 is NH2 or N(alkyl)2. In still other exemplary embodiments RA is hydrogen or methyl. In yet other embodiments of interest R9a is hydrogen, methyl or ethyl. In certain other embodiments, q is 0.
VI. Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof): 
wherein RA is hydrogen, oxygen, or an alkyl or heteroalkyl moiety;
RC is hydrogen; halogen, cyano or an alkyl or heteroalkyl moiety;
each occurrence of R9 and R5 is independently hydrogen, halogen, alkyl or heteroalkyl;
R7 is hydrogen; alkyl; heteroalkyl; aryl; heteroaryl; cyano; or xe2x80x94ZRJ, wherein each occurrence of Z is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRK, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94COOxe2x80x94, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, xe2x80x94NRLRM, or an alkyl, heteroalkyl, aryl or heteroaryl moiety;
AK is (CRPCRQ);
each occurrence of RP and RQ is independently hydrogen or an alkyl or heteroalkyl moiety;
q is an integer from 0 to 5;
p is an integer from 0-3;
r is an integer from 0-2;
R9a is hydrogen; or an alkyl or heteroalkyl moiety;
K is O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NR1xe2x80x94, or a chemical bond linking R1 to P, each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
x is 0-6;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.
In certain embodiments, R9 and R5 are each hydrogen. In still other embodiments R7 is NH2 or N(alkyl)2. In still other exemplary embodiments RA is hydrogen or methyl. In yet other embodiments of interest R9a is hydrogen, methyl or ethyl. In certain other embodiments, q is 0.
VII. Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof): 
wherein RA is hydrogen, oxygen, or an alkyl or heteroalkyl moiety;
RB is an alkyl, heteroalkyl, aryl or heteroaryl moiety;
RC is hydrogen; halogen, cyano or an alkyl or heteroalkyl moiety;
each occurrence of R9 and R5 is independently hydrogen, halogen, alkyl or heteroalkyl;
p is an integer from 0-3;
r is an integer from 0-2;
R9a is hydrogen; or an alkyl or heteroalkyl moiety;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted;
and wherein either one or both of RB and RD comprises or is substituted with a phosphorus-containing moiety of Series II: 
wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2; and each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6;
PCM is a phosphorus-containing moiety of Series I, Series Ia, Series Ib; or Series Ic, and m is an integer from 0-3, t is an integer from 1-3, and the sum of m+t is an integer from 1-5.
In certain embodiments, either one or both of RB and RD is independently substituted with one or more occurrences of hydrogen, halogen, cyano, hydroxy, or alkoxy. In certain other embodiments each occurrence of R9 and R5 are each hydrogen. In still other exemplary embodiments RA is hydrogen or methyl. In yet other embodiments of interest R9a is hydrogen, methyl or ethyl.
VIII. Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof): 
wherein RA is hydrogen, oxygen or an aliphatic or heteroaliphatic moiety;
RB is an aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety;
RD is an aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety;
wherein in each of the foregoing groups each aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted;
and wherein either one or both of RB and RD comprises or is substituted with a phosphorus containing moiety of Series II: 
wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2; and each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6;
PCM is a phosphorus-containing moiety of Series I, Series Ia, Series Ib; or Series Ic, and m is an integer from 0-3, t is an integer from 1-3, and the sum of m+t is an integer from 1-5.
In certain embodiments, either one or both of RB and RD is independently substituted with one or more occurrences of hydrogen, halogen, cyano, hydroxy, or alkoxy. In certain other embodiments each occurrence of R9 and R5 are each hydrogen. In still other exemplary embodiments RA is hydrogen or methyl. In yet other embodiments of interest R9a is hydrogen, methyl or ethyl.
IX. Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof): 
wherein RA is an aliphatic or heteroaliphatic moiety;
RB is an aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety;
R3 independently represents from 0-3 substituents selected from hydrogen; halogen; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, and sulfonamido; wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2;
t is an integer from 1-3;
s is an integer from 0-4; wherein the sum t+s is 1-5; and
wherein PCM is a phosphorus-containing moiety selected from Series I: 
wherein each occurrence of K is independently O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1);
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94 or (M)x;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6; and
each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted.
X. Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof): 
wherein RA is an aliphatic or heteroaliphatic moiety;
RD is an aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety;
R3 independently represents from 0-3 substituents selected from hydrogen; halogen; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, and sulfonamido; wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2;
t is an integer from 1-3;
s is an integer from 0-3, wherein the sum t+s is 1-5; and
wherein PCM is a phosphorus-containing moiety selected from Series I: 
wherein each occurrence of K is independently O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1);
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94 or (M)x;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6; and
each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted.
It will be appreciated that, in certain exemplary embodiments, for each of the foregoing compounds described in sections VII-X above, either or both of RB and RD (or specific substituents as further defined for RB and RD, e.g., AR, phenyl) independently comprises or is substituted with a phosphorus-containing moiety of Series IIa: 
wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1); wherein each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6;
m is an integer from 0-3; and
PCM is a phosphorus-containing moiety of Series I, Series Ia, Series Ib or Series Ic.
In certain other exemplary embodiments, PCM is a phosphorus-containing moiety of Series Ic: 
wherein each occurrence of R1 is independently hydrogen, alkyl or aryl;
each occurrence of R4 is independently alkyl or aryl;
each occurrence of R6 is independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; and
each occurrence of R8 is independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, or a prodrug moiety.
In certain other embodiments, R6 is hydrogen, lower alkyl, ORL or NRLRM; wherein each occurrence of RL and RM is independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety. In certain other embodiments, R6 is hydrogen, methyl, ethyl, OH or NH2. In certain embodiments, R8 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl or a prodrug moiety. In still other embodiments, R8 is hydrogen, methyl, ethyl, or a prodrug moiety.
In certain other exemplary embodiments, for each of the foregoing compounds described in sections VII-X above, either or both of RB and RD (or specific substituents as further defined for RB and RD, e.g., AR, phenyl) independently comprises or is substituted with a phosphorus-containing moiety of Series IIb: 
wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2;
each occurrence of R2 is independently R1, xe2x80x94PK(YR1)(YR1), xe2x80x94SO2(YR1) or xe2x80x94C(O)(YR1);
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x;
each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6; and
m is an integer from 0-3.
In still other exemplary embodiments, for each of the foregoing compounds described in sections VII-X above, either or both of RB and RD (or specific substituents as further defined for RB and RD, e.g., AR, phenyl) independently comprises or is substituted with a phosphorus-containing moiety of Series III: 
wherein each occurrence of R3 is independently hydrogen; halogen; xe2x80x94CN; NO2; N3; R1; xe2x80x94GR1; xe2x80x94CO(Yxe2x80x2R1); xe2x80x94NR1(Yxe2x80x2R1); S(O)2(Yxe2x80x2R1); wherein each occurrence of Yxe2x80x2 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94COOxe2x80x94 or S(O)2; each occurrence of G is independently absent, or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR1xe2x80x94, S(O)2, or (M)x; and m is an integer from 0-4;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
each occurrence of x is independently an integer from 0-6;
each occurrence of R6 is independently hydrogen, aliphatic, heteroaliphatic, aryl or heteroaryl moiety; and
each occurrence of R8 is independently hydrogen, an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or a prodrug moiety;
wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.
XI. Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof): 
wherein RA is an aliphatic or heteroaliphatic moiety;
each occurrence of K is independently O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
x is an integer from 0-6;
each occurrence of R3 independently represents hydrogen; halogen; C1-6 alkyl; and C1-6 alkyloxy;
each occurrence of s is independently an integer from 0-3; and
wherein in each of the foregoing groups each aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.
XII. Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof): 
wherein RA is an aliphatic or heteroaliphatic moiety;
each occurrence of K is independently O or S;
each occurrence of Y is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR1xe2x80x94, or a chemical bond linking R1 to P;
each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;
each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-Mxe2x80x2 moiety may be electronically saturated or unsaturated;
x is an integer from 0-6;
each occurrence of R3 independently represents hydrogen; halogen; C1-6 alkyl; and C1-6 alkyloxy;
each occurrence of s is independently an integer from 0-3; and
wherein in each of the foregoing groups each aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.
In certain embodiments, for each of the compounds as described above and herein, Y is a chemical bond linking the phosphorus atom to R1. In certain other embodiments Y is an oxygen atom. In still other embodiments, Y is a chemical bond linking the phosphorus atom to R1 and R1 is an alkyl group having 1-6 carbon atoms. In yet other embodiments of the compounds as generally described above, RA is hydrogen or an aliphatic or heteroaliphatic moiety. In certain other subsets, K is O. In still other embodiments, x is 0. In yet other embodiments, x is 1-4 and M is xe2x80x94CH2xe2x80x94.
This invention also provides a pharmaceutical preparation comprising at least one of the foregoing compounds or a pharmaceutically acceptable derivative thereof, as inhibitors of bone resorption by osteoclasts, as inhibitors of tumor growth and tumor metastatsis, for the treatment and prophylaxis of diseases or undesirable conditions which are mediated by a kinase inhibited by said compound, as inhibitors of vascular permeability and/or angiogenesis, and at least one pharmaceutically acceptable excipient or additive. Preferably the excipient of additive is pharmaceutically innocuous.
The invention further provides a method for inhibiting bone resorption, inhibiting tumor growth and/or tumor metastasis, inhibiting vascular permeability and/or angiogenesis, or for the treatment and prevention of diseases or undesirable conditions which are mediated by a kinase inhibited by one of the foregoing compounds. The method involves administering a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a human or animal in need of it. Such administration constitutes a method for inhibiting bone resorption by osteoclasts, for inhibiting tumor growth and/or tumor metastasis or other proliferative disease, or for inhibiting vascular permeability and/or angiogenesis. Generally speaking, such administration comprises a method for the treatment and prophylaxis of diseases which are mediated by a kinase inhibited by one of the foregoing compounds or a pharmaceutically acceptable derivative thereof.
The compounds provided by this invention are also useful as standards and reagents in characterization of various kinases, especially, but not limited to Src family kinases; the study of the role of such kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; the comparative evaluation of new kinase inhibitors; the study of various cancers in cell lines and animal models; and the study of bone biology, including the competing forces of resorption and generation of bone.
3. Compounds and Definitions
This invention provides a new family of compounds with a range of biological properties. Compounds of this invention have biological activities relevant for the treatment of diseases including bone related disorders, disorders related to cellular proliferation (e.g., cancer) and disorders related to increased vascular permeability and/or angiogenesis. More generally, the compounds are useful in the regulation of signal transduction pathways. For example, certain compounds of the invention are useful for inhibiting tyrosine kinases, including without limitation receptor-type tyrosine kinases such as those of the HER (e.g. EGFR, HER2, HER3 and HER4), PDGF and FLK families (including, e.g., VEGF-R1 and VEGF-R2) as well as non-reecptor-type tyrosine kinases such as those of the Src and abl subfamilies, again as non-limiting examples.
Compounds of this invention include those described herein, and illustrated in part by the various classes, subclasses and species disclosed elsewhere herein.
Some of the compounds contain one or more asymmetric centers. Thus, compounds of the invention and pharmaceutical compositions thereof may be in the form of an individual enantiomer or diastereomer isomer, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the invention are in the form of a single enantiomer or diastereomer, substantially free from other enantiomers or diastereomers (i.e., in a form containing less than 10%, preferably less than 5% and in some cases even more preferably less than 1% of one or more other enantiomers or diasteriomers, by weight or molarity. In certain other embodiments, a mixture of stereoisomers or diastereomers are provided.
Additionally, the present invention provides pharmaceutically acceptable derivatives of the inventive compounds, and methods of treating a subject using these compounds, pharmaceutical compositions containing one or more of the compounds or a pharmaceutically acceptable derivative thereof, or either of these in combination with one or more additional therapeutic agents. The phrase, xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d, as used herein, denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof. Pharmaceutically acceptable derivatives thus include among others pro-drugs. A pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety which is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species. An example of a pro-drug is an ester which is cleaved in vivo to yield a compound of interest. Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.
Certain compounds of this invention, and definitions of specific functional groups are also described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in xe2x80x9cOrganic Chemistryxe2x80x9d, Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference. Furthermore, it will be appreciated by one of ordinary skill in the art that the synthetic methods, as described herein, can utilize a variety of protecting groups. By the term xe2x80x9cprotecting groupxe2x80x9d, has used herein, it is meant that a particular functional group, e.g., xe2x80x94OH, xe2x80x94NHxe2x80x94, xe2x80x94SH, xe2x80x94CHO, xe2x80x94COOH, xe2x80x94Cxe2x95x90Oxe2x80x94, xe2x80x94P(xe2x95x90O)(OH)xe2x80x94, etc., is temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound. In preferred cases, a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; is selectively removable in practicable yield without loss of other functional groups of the protected molecule; forms a separable derivative (more preferably without the generation of new stereogenic centers); and has a minimum of additional functionality to avoid further sites of reaction. Exemplary protecting groups are detailed herein, however, it will be appreciated that the present invention is not limited to these protecting groups; rather, a variety of alternative protecting groups can be readily identified based on the above criteria combined with availability, user familiarity, convenience, etc. and utilized in the method of the present invention. Additionally, a variety of protecting groups are described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d Third Ed. Greene, T. W. and Wuts, P. G., Eds., John Wiley and Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
As described herein, compounds of the invention may be substituted with any number of substituents or functional groups, such as are illustrated in connection with particular classes, subclasses and species of the invention. In general, the term xe2x80x9csubstitutedxe2x80x9d and xe2x80x9csubstituentxe2x80x9d, whether preceded by the term xe2x80x9coptionallyxe2x80x9d or not, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term xe2x80x9csubstitutedxe2x80x9d encompasses all permissible substituents of organic compounds. Substituents are discussed in detail below and illustrated throughout this document. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds, useful in the treatment of various disorders as described herein, e.g. for bone related disorders, cancer or other disorders related to excessive cellular proliferation, disorders related to increases in vascular permeability, and/or more generally, disorders related to cell signalling. The term xe2x80x9cstablexe2x80x9d, as used herein, refers to compounds that possess stability sufficient to allow their production, detection and preferably their recovery, purification and use for one or more of the purposes disclosed herein.
The term xe2x80x9caliphaticxe2x80x9d, as used herein, includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. The term includes, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, as used herein, the term xe2x80x9calkylxe2x80x9d includes straight, branched and cyclic alkyl groups. An analogous convention applies to other generic terms such as xe2x80x9calkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d and the like. Furthermore, as used herein, the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d and the like encompass both substituted and unsubstituted groups. The term xe2x80x9clowerxe2x80x9d as applied to alkyl or other aliphatic groups indicates a group having 1-6 carbon atoms (which may be substituted or unsubstituted as specified).
Unless otherwise specified, the alkyl, alkenyl and alkynyl groups contain 1-20 aliphatic carbon atoms. In some embodiments, they contain 1-10 aliphatic carbon atoms. In other embodiments, they contain 1-8 aliphatic carbon atoms. In still other embodiments, they contain 1-6 aliphatic carbon atoms, and in yet other embodiments, 1-4 carbon atoms. Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, allyl, n-propyl, isopropyl, cyclopropyl, xe2x80x94CH2-cyclopropyl, methallyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, xe2x80x94CH2-cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, xe2x80x94CH2-cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, xe2x80x94CH2-cyclohexyl moieties and the like, which again, may bear one or more substituents. Benzyl, phenethyl, heteroaromatic analogs, and substituted derivatives of such moieties are thus considered substituted aliphatic moieties. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
The term xe2x80x9calkoxyxe2x80x9d, or xe2x80x9cthioalkylxe2x80x9d as used herein refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom or through a sulfur atom. Examples of alkoxy, include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy. Examples of thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
The term xe2x80x9calkylaminoxe2x80x9d refers to a group having the structure xe2x80x94NHRxe2x80x2 wherein Rxe2x80x2 is alkyl, as defined herein. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, iso-propylamino and the like. In certain embodiments, C1-C3 alkylamino groups are utilized in the present invention.
Some examples of substituents for various optionally substituted moieties of compounds of the invention include, but are not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; xe2x80x94OH; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CF3; xe2x80x94CH2CF3; xe2x80x94CHCl2; xe2x80x94CH2OH; xe2x80x94CH2CH2OH; xe2x80x94CH2NH2; xe2x80x94CH2SO2CH3; xe2x80x94C(O)Rx; xe2x80x94CO2(Rx); xe2x80x94CON(Rx)2; xe2x80x94OC(O)Rx; xe2x80x94OCO2Rx; xe2x80x94OCON(Rx)2; xe2x80x94N(Rx)2; xe2x80x94S(O)2Rx; xe2x80x94SO2NRx2; and xe2x80x94NRx(CO)Rx moieties-wherein each occurrence of Rx is a group independently chosen from: H; an aliphatic or heteroaliphatic moiety which may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic; and an optionally substituted aryl or heteroaryl moiety. In addition, substituents include phosphorus-containing moieties, as defined herein including the various illustrative series of phosphorus-containing moieties (e.g. Series I, Ia, Ib, Ic, II, Ia, IIb, etc.). Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein. The foregoing is intended to be encompassed by references to xe2x80x9csubstituentsxe2x80x9d and xe2x80x9csubstitutedxe2x80x9d in this document.
The terms xe2x80x9carylxe2x80x9d and xe2x80x9cheteroarylxe2x80x9d, as used herein, refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted. It will also be appreciated that aryl and heteroaryl moieties, as defined herein may be attached via an alkyl or heteroalkyl moiety and thus also include -(alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)aryl, and -(heteroalkyl)heteroaryl moieties. Thus, as used herein, the phrases xe2x80x9caryl or heteroarylxe2x80x9d and xe2x80x9caryl, heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)aryl, and -(heteroalkyl)heteroarylxe2x80x9d are interchangeable. Substituents for exemplary aryl and heteroaryl moieties include, but are not limited to, any of the substitutents previously mentioned or alluded to. In certain embodiments, xe2x80x9carylxe2x80x9d refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. In certain embodiments of the present invention, the term xe2x80x9cheteroarylxe2x80x9d, as used herein, refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
It will be appreciated that aryl and heteroaryl groups can be unsubstituted or substituted, wherein substitution includes replacement of one or more (e.g. 1, 2 or 3) of the hydrogen atoms thereon with substituents such as are described herein or illustrated in any of the illustrative examples herein.
The term xe2x80x9ccycloalkylxe2x80x9d, as used herein, refers specifically to groups having three to ten, preferably three to seven carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of other aliphatic, heteroaliphatic or hetercyclic moieties, may optionally be substituted as previously described.
The term xe2x80x9cheteroaliphaticxe2x80x9d, as used herein, refers to aliphatic moieties which contain one or more oxygen, sulfur, nitrogen, phosphorous or silicon atoms, e.g., in place of carbon atoms. Heteroaliphatic moieties may be substituted or unsubstituted, branched, unbranched, cyclic or acyclic, and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc.
The terms xe2x80x9chaloxe2x80x9d and xe2x80x9chalogenxe2x80x9d as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.
The term xe2x80x9chaloalkylxe2x80x9d denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.
The term xe2x80x9cheterocycloalkylxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d, as used herein, refers to a non-aromatic 5-, 6- or 7-membered ring or a polycyclic group, including, but not limited to a bi- or tri-cyclic group, having one to four heteroatoms independently chosen from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quatemized, and (iv) any of the above heterocyclic rings may be fused to a benzene ring. Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. The heterocyclic moiety may be substituted or unsubstituted.
As used herein, the phrase, xe2x80x9cphosphorus-containing moietyxe2x80x9d includes, but is not limited to, phosphites, phosphonites, phosphenites, phosphines, phosphates, phosphonates, phosphenates, phosphine oxides, bisphosphonates, thiophosphates, thiophosphonates, thiophosphenates, thiophosphine oxides, mono- or (where permitted) di- or tri-amides and esters of any of the foregoing as well as the phosphorus-containing moieties disclosed in Series I, Ia, Ib,Ic, II, IIa, IIb or III or otherwise described herein, including in the accompanying text and illustrative classes, subclasses, and species of compounds disclosed herein.
4. Synthetic Overview
The practitioner has a a well-established literature of quinolinone chemistry to draw upon, in combination with the information contained herein, for guidance on synthetic strategies, protecting groups, and other materials and methods useful for the synthesis of the compounds of this invention, including compounds containing the various RA, RB, RC and RD substituents.
The various patent documents and other references cited herein provide helpful background information on producing variously analogously substituted quinolinones or relevant intermediates, as well as information on formulation, uses, and administration of prior quinolinones which may be of interest.
Moreover, the practitioner is directed to the specific guidance and examples provided in this document relating to the various phosphorus-containing moieties and intermediates containing them.
Numerous suitable prodrug moieties, and information concerning their selection, synthesis and use are well known, beginning with lower alkyl esters of phosphonates and related moieties. Other prodrug moieties of interest include, among others, the following:
Other prodrug moieties of interest that can be attached to primary or secondary amine-containing functionality at groups RB, RC, and RD include the following:
Uses, Formulations, Administration
Pharmaceutical Compositions
The inclusion of a phosphorus-containing moiety in the design of the compounds of this invention can impart interesting functional characteristics to the compounds. For instance, depending in some cases on the choice of phosphorus-containing moiety and/or its location in the compound, characteristics of the compounds such as in vitro or in vivo potency, ClogP, aqueous solubility, ability to penetrate cells, and ability to target bone tissue may be desirably affected. As discussed above the novel compounds of this invention have biological properties which make them of interest for the treatment of bone disorders, disorders related to cellular proliferation (e.g., cancer), and disorders resulting from increased vascular permeability and/or angiogenesis.
Thus, in one aspect of the invention, compositions are provided which contain at least one of the compounds described herein (or a prodrug, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative thereof), and optionally comprise one or more pharmaceutically acceptable excipients, diluents and/or carriers.
In certain embodiments, these compositions optionally further comprise, or are administered conjointly with, one or more additional therapeutic agents. For example, the additional therapeutic agent may be an anticancer agent, an agent for the treatment of a bone disorder, or an agent for the treatment of disorders related to increased vascular permeability and/or angiogenesis, as discussed in more detail herein.
As noted previously, certain of the compounds of this invention can exist in free form, or where appropriate, as a pharmaceutically acceptable derivative thereof. As used herein, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of various classes of compounds including amines, carboxylic acids, phosphonates and others are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, inalonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
Additionally, as used herein, the term xe2x80x9cpharmaceutically acceptable esterxe2x80x9d refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters includes formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
Furthermore, the term xe2x80x9cpharmaceutically acceptable prodrugsxe2x80x9d as used herein refers to those prodrugs of the compounds of this invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with umdue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
As described above, the pharmaceutical compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington""s Pharmaceutical Sciences, Fifteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1975) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the anti-viral compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer""s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
Uses of Compounds of the Invention
As discussed herein, compounds of this invention may be used for inhibiting the activity of certain tyrosine kinases, and thus are useful generally for disorders mediated by those Or inases, and in certain embodiments, are useful for the treatment of proliferative disorders including among others certain cancers. Additionally, various compounds of the invention may be used to inhibit osteoclast activity and/or promote bone-forming activity and to thus tilt the balance of bone resorption and bone growth positively, ie., away from net bone loss. Furthermore, certain inventive compounds are useful in inhibiting angiogenic acitivity. As such, the compounds of the invention may be useful in the treatment of bone disorders, proliferative disorders, including, but not limited to cancer, and disorders related to increased angiogenic activity.
Thus, administering to a subject in need thereof a therapeutically effective amount of a compound of the invention, or a composition containing such compound or a pharmaceutically acceptable derivative thereof, provides a method for the treatment of those disorders. A xe2x80x9ctherapeutically effective amountxe2x80x9d is an amount effective for detectably ameliorating the disorder, e.g., an amount effective for detectably killing or inhibiting the growth of tumor cells; for inhibiting osteoclast activity, slowing bone resorption, increasing bone growth or reducing serum calcium levels; or for inhibiting antiangiogenesis or edema or a manifestation thereof.
The compounds and compositions, according to the method of the present invention, may be administered using any dosage amount and any route of administration effective for the treatment of disorders in question. The exact dosage amount will vary from subject to subject, depending on the species, age, and general condition of the subject, the nature and severity of the disorder, the overall efficacy of the agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression xe2x80x9cdosage unit formxe2x80x9d as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
Furthermore, after formulation with an appropriate pharmaceutically acceptable carrier in a desired dosage, the pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agarxe2x80x94agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
As discussed above, in one aspect, the compounds of this invention are useful as anticancer agents, and thus may be useful in the treatment of cancer, by effecting tumor cell death or inhibiting the growth of tumor cells. In certain embodiments, compounds of the invention are useful as inhibitors of EGF. Without wishing to be bound by any particular theory, it is known that the EGF family of receptor tyrosine kinases (and certain other receptor tyrosine kinases) are frequently present in common human cancers such as breast cancer (Sainsbury et. al., Brit. J. Cancer, 1988, 58, 458; Guerin et al., Oncogene Res., 1988, 3, 21 and Klijn et al., Breast Cancer Res. Treat., 1994, 29, 73), non-small cell lung cancers (NSCLCs) including adenocarcinomas (Cerny et al., Brit. J. Cancer, 1986, 54, 265; Reubi et al., Int. J. Cancer, 1990, 45, 269; and Rusch et al., Cancer Research, 1993, 53, 2379) and squamous cell cancer of the lung (Hendler et al., Cancer Cells, 1989, 7, 347), bladder cancer (Neal et. al., Lancet, 1985, 366), oesophageal cancer (Mukaida et al., Cancer, 1991, 68, 142), gastrointestinal cancer such as colon, rectal or stomach cancer (Bolen et al., Oncogene Res., 1987, 1, 149), cancer of the prostate (Visakorpi et al., Histochem. J., 1992, 24, 481), leukaemia (Konaka et al., Cell, 1984, 37, 1035) and ovarian, bronchial or pancreatic cancer (European Patent Specification No. 0400586). It is also known that EGF receptors which possess tyrosine kinase activity are overexpressed in many human cancers such as brain, lung squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynaecological and thyroid tumours. Accordingly it has been recognised that an inhibitor of receptor tyrosine kinases should be of value as a selective inhibitor of the growth of mammalian cancer cells (Yaish et al. Science, 1988, 242, 933).
In general, the inventive anticancer agents are useful in the treatment of cancers and other proliferative disorders, including, but not limited to breast cancer, cervical cancer, colon, stomach and rectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin""s lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, head, neck, oesophageal, gynaecological, thyroid, and gastric cancer, to name a few. In certain embodiments, the inventive anticancer agents are active against leukemia cells and melanoma cells, and thus are useful for the treatment of leukemias (e.g., myeloid, lymphocytic, myelocytic and lymphoblastic leukemias) and malignant melanomas. In still other embodiments, the inventive anticancer agents are active against solid tumors and also kill and/or inhibit the growth of multidrug resistant cells (MDR cells).
It will also be appreciated that the compounds and pharmaceutical compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another anticancer agent), or they may achieve different effects (e.g., control of any adverse effects).
For example, other therapies or anticancer agents that may be used in combination with the inventive anticancer agents of the present invention include surgery, radiotherapy (in but a few examples, xcex3-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and Megestrol), to name a few. For a more comprehensive discussion of updated cancer therapies see, http://www.nci.nih.gov/, a list of the FDA approved oncology drugs at http://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck Manual, Seventeenth Ed. 1999, the entire contents of which are hereby incorporated by reference.
As discussed above, in another aspect, the compounds of this invention are useful in the selective treatment or prevention of bone disorders, and may effect treatment via inhibition of osteoclast activity, promotion of osteoblast activity, or promotion or inhibition of other cellular events necessary for healthy bone metabolism. In certain preferred embodiments, these compounds are useful for the treatment or prevention of diseases and conditions associated with bone metabolic disorders such as osteoclast overactivity. In still other embodiments, the compounds of this invention are targeted Src kinase inhibitors and thus inhibit bone resorption by osteoclasts.
The present invention therefore provides a method for the treatment, prophylaxis, and/or prevention of bone and other related disorders which method comprises the administration of an effective non-toxic amount of an inventive compound, or a pharmaceutically composition thereof. As mentioned above, although the inventive compounds effect treatment via several mechanisms, (i.e. inhibition of osteoclast activity, promotion of osteoblast activity, or regulation of other cellular events necessary for healthy bone metabolism), in certain preferred embodiments, these compounds are selective inhibitors of osteoclast activity.
In a further aspect, the present invention provides an inhibitor of mammalian osteoclasts, for example any one of the compounds of this invention or a pharmaceutical composition thereof. In still another aspect, the present invention provides compounds or pharmaceutical compositions that are selective Src kinase inhibitors. In particular, the method of present invention comprises providing any one of the compounds of this invention or a pharmaceutically composition thereof, for use in the treatment of and/or prophylaxis of osteoporosis and related osteopenic diseases.
It will be appreciated that, in addition to the treatment or prevention of osteoporosis, particularly osteoporosis associated with the peri and post menopausal conditions, the present invention also contemplates the treatment and prophylaxis or prevention of Paget""s disease, hypercalcemia associated with bone neoplasms and other types of osteoporotic diseases and related disorders, including but not limited to involutional osteoporosis, Type I or postmenopausal osteoporosis, Type II or senile osteoporosis, juvenile osteoporosis, idiopathic osteoporosis, endocrine abnormality, hyperthyroidism, hypogonadism, ovarian agensis or Turner""s syndrome, hyperadrenocorticism or Cushing""s syndrome, hyperparathyroidism, bone marrow abnormalities, multiple myeloma and related disorders, systemic mastocytosis, disseminated carcinoma, Gaucher""s disease, connective tissue abnormalities, osteogenesis imperfecta, homocystinuria, Ehlers-Danlos syndrome, Marfan""s syndrome, Menke""s syndrome, immobilization or weightlessness, Sudeck""s atrophy, chronic obstructive pulmonary disease, chronic heparin administration, and chronic ingestion of anticonvulsant drugs.
In yet another embodiment, in addition to the treatment or prevention of osteoporosis or cancer, the present invention can be utilized to inhibit increases in vascular permeability. For example, certain compounds are tested for the ability to inhibit the tyrosine kinase activity associated with the VEGF receptors such as Flt and/or KDR and for their ability to inhibit angiogenesis and/or increased vascular permeability. Additionally, these compounds can be tested for the ability to inhibit the tyrosine kinase activity associated with Src and for their ability to inhibit angiogenesis and/or increased vascular permeability. These properties may be assessed, for example, using one or more of the procedures set out below. Thus according to this aspect of the invention there is provided a method for reducing vascular permability in a subject comprising administering a compound of Formula I, as described herein and as described by the various classes and subclasses.
It will be appreciated that, similarly to the anticancer treatment and treatment for osteoporosis, as also described herein, the antiangiogenic and/or vascular permeability reducing treatment defined herein may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer. In medical oncology the other component(s) of such conjoint treatment in addition to the antiangiogenic end/or vascular permeability reducing treatment defined herein may be: surgery, radiotherapy or chemotherapy. Such chemotherapy may cover three main categories of therapeutic agent:
(1) other antiangiogenic agents that work by different mechanisms from those defined hereinbefore (for example linomide, angiostatin, razoxin, thalidomide);
(ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene), progestogens (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrazole, vorazole, exemestane), antiprogestogens, antiandrogens (for example flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (for example goserelin acetate, luprolide), inhibitors of testosterone 5.alpha.-dihydroreductase (for example finasteride), anti-invasion agents (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function) and inhibitors of growth factor function, (such growth factors include for example EGF, FGFs, platelet derived growth factor and hepatocyte growth factor such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors and serine/threonine kinase inhibitors); and
(iii) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as antimetabolites (for example antifolates like methotrexate, fluoropyrimidines like 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside); antitumour antibiotics (for example anthracyclines like doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for example cisplatin, carboplatin); alkylating agents (for example nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic agents (for example vinca alkaloids like vincristine and taxoids like taxol, taxotere); topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan).
As stated above, in another embodiment of the invention, the compounds defined in the present invention are of interest for their antiangiogenic and/or vascular permeability reducing effects. Such compounds of the invention are expected to be useful in a wide range of disease states including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi""s sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation and ocular diseases with retinal vessel proliferation. In particular, such compounds of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the colon, breast, prostate, lungs and skin. More particularly such compounds of the invention are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with VEGF, especially those tumours which are significantly dependent on VEGF for their growth and spread, including for example, certain tumours of the colon, breast, prostate, lung, vulva and skin.
Treatment Kits
In other embodiments, the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention. In general, the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Such kits are especially suited for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a number of unit dosages, and may also include a card having the dosages oriented in the order of their intended use. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered. Alternatively, placebo dosages, or calcium dietary supplements, either in a form similar to or distinct from the substituted purine dosages, can be included to provide a kit in which a dosage is taken every day. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art.
The following examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and the equivalents thereof.